Advertisement

Tumor Biology

, Volume 36, Issue 5, pp 3301–3308 | Cite as

LYTAK1, a novel TAK1 inhibitor, suppresses KRAS mutant colorectal cancer cell growth in vitro and in vivo

Research Article

Abstract

KRAS mutation in colorectal cancer (CRC) activates transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) to promote tumor progression. In the current study, we explored the potential effect of LYTAK1, a novel TAK1 inhibitor, against KRAS mutant CRC cells in vitro and in vivo. We found that LYTAK1 dose-dependently inhibited KRAS mutant CRC cell (HT-29 and SW-620 lines) growth, and induced cell cycle G1-S arrest. Further, LYTAK1 activated apoptosis in HT-29 cells and SW-620 cells, and apoptosis inhibitors almost reversed LYTAK1-mediated growth inhibition. While in KRAS wild-type (WT) CRC cell lines (DLD-1 and HCT-116), LYTAK1 had almost no effect on cell growth, cell cycle progression, or cell apoptosis. In KRAS mutant HT-29 cells and SW-260 cells, LYTAK1 blocked TAK1 activation or phosphorylation at Thr-184/187. Activation of nuclear factor κB (NF-κB) in these cells, detected by phosphorylations of p65 and IκB kinase α (IKKα) as well as expression of NF-κB-regulated gene cyclin D1, was significantly inhibited by LYTAK1. Further, LYTAK1 treatment resulted in downregulation of β-catenin and Wnt response gene Axin 2, indicating Wnt inactivation. In vivo, oral LYTAK1 significantly inhibited HT-29 xenograft growth in nude mice. Together, these results show that LYTAK1 inhibits KRAS mutant CRC cell growth both in vitro and in vivo. LYTAK1 might be investigated as a novel agent against CRC with KRAS mutation.

Keywords

Colorectal cancer KRAS Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) LYTAK1 and signaling 

Notes

Acknowledgments

This study was supported by the National Natural Science Foundation of China (81372433 and 81472920), the Natural Science Foundation of Jiangsu Province of China (BK20131149), and the Suzhou Administration of Science & Technology (SYS201360)

Conflicts of interest

None

References

  1. 1.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.CrossRefPubMedGoogle Scholar
  2. 2.
    Westwood M, van Asselt T, Ramaekers B, Whiting P, Joore M, Armstrong N, et al. Kras mutation testing of tumours in adults with metastatic colorectal cancer: a systematic review and cost-effectiveness analysis. Health Technol Assess. 2014;18:1–132.CrossRefGoogle Scholar
  3. 3.
    Arrington AK, Heinrich EL, Lee W, Duldulao M, Patel S, Sanchez J, et al. Prognostic and predictive roles of KRAS mutation in colorectal cancer. Int J Mol Sci. 2012;13:12153–68.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Siddiqui AD, Piperdi B. KRAS mutation in colon cancer: a marker of resistance to EGFR-I therapy. Ann Surg Oncol. 2010;17:1168–76.CrossRefPubMedGoogle Scholar
  5. 5.
    Fakih MM. Kras mutation screening in colorectal cancer: from paper to practice. Clin Colorectal Cancer. 2010;9:22–30.CrossRefPubMedGoogle Scholar
  6. 6.
    Rinehart J, Adjei AA, Lorusso PM, Waterhouse D, Hecht JR, Natale RB, et al. Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol. 2004;22:4456–62.CrossRefPubMedGoogle Scholar
  7. 7.
    Sakurai H. Targeting of TAK1 in inflammatory disorders and cancer. Trends Pharmacol Sci. 2012;33:522–30.CrossRefPubMedGoogle Scholar
  8. 8.
    Martin SE, Wu ZH, Gehlhaus K, Jones TL, Zhang YW, Guha R, et al. Rnai screening identifies TAK1 as a potential target for the enhanced efficacy of topoisomerase inhibitors. Curr Cancer Drug Targets. 2011;11:976–86.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Melisi D, Xia Q, Paradiso G, Ling J, Moccia T, Carbone C, et al. Modulation of pancreatic cancer chemoresistance by inhibition of TAK1. J Natl Cancer Inst. 2011;103:1190–204.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Singh A, Sweeney MF, Yu M, Burger A, Greninger P, Benes C, et al. TAK1 inhibition promotes apoptosis in KRAS-dependent colon cancers. Cell. 2012;148:639–50.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Ray DM, Myers PH, Painter JT, Hoenerhoff MJ, Olden K, Roberts JD. Inhibition of transforming growth factor-beta-activated kinase-1 blocks cancer cell adhesion, invasion, and metastasis. Br J Cancer. 2012;107:129–36.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Chen MB, Wei MX, Han JY, Wu XY, Li C, Wang J, et al. Microrna-451 regulates AMPK/mTORC1 signaling and fascin1 expression in HT-29 colorectal cancer. Cell Signal. 2014;26:102–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Di Nicolantonio F, Arena S, Tabernero J, Grosso S, Molinari F, Macarulla T, et al. Deregulation of the PI3k and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest. 2010;120:2858–66.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Wang S, Liu Z, Wang L, Zhang X. NF-kappab signaling pathway, inflammation and colorectal cancer. Cell Mol Immunol. 2009;6:327–34.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Vaiopoulos AG, Athanasoula K, Papavassiliou AG. NF-kappab in colorectal cancer. J Mol Med (Berl). 2013;91:1029–37.CrossRefGoogle Scholar
  16. 16.
    Guttridge DC, Albanese C, Reuther JY, Pestell RG, Baldwin Jr AS. NF-kappab controls cell growth and differentiation through transcriptional regulation of cyclin D1. Mol Cell Biol. 1999;19:5785–99.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    McConnell BB, Yang VW. The role of inflammation in the pathogenesis of colorectal cancer. Curr Color Cancer Rep. 2009;5:69–74.CrossRefGoogle Scholar
  18. 18.
    Ishizuka M, Nagata H, Takagi K, Kubota K. Influence of inflammation-based prognostic score on mortality of patients undergoing chemotherapy for far advanced or recurrent unresectable colorectal cancer. Ann Surg. 2009;250:268–72.CrossRefPubMedGoogle Scholar
  19. 19.
    Kraus S, Arber N. Inflammation and colorectal cancer. Curr Opin Pharmacol. 2009;9:405–10.CrossRefPubMedGoogle Scholar
  20. 20.
    Itzkowitz SH, Yio X. Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Liver Physiol. 2004;287:G7–G17.CrossRefPubMedGoogle Scholar
  21. 21.
    Li Q, Verma IM. NF-kappab regulation in the immune system. Nat Rev Immunol. 2002;2:725–34.CrossRefPubMedGoogle Scholar
  22. 22.
    Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. Cell. 2000;103:311–20.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  1. 1.The Core Laboratory of the Suzhou Cancer Center and Department of RadiotherapySuzhou Hospital Affiliated to Nanjing Medical UniversitySuzhouChina
  2. 2.Department of Urologythe Second Affiliated Hospital of Nantong UniversityNantongChina
  3. 3.Lishui Center HospitalLishuiChina
  4. 4.The Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Jiangsu Institute of HematologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
  5. 5.School of Radiation Medicine and ProtectionMedical College of Soochow UniversitySuzhouChina
  6. 6.Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education InstitutionsSuzhouChina

Personalised recommendations